Linezolid, Therapeutic Drug Monitoring (TDM), Tuberculosis Multi Drug Resistant Active
Conditions
Keywords
linezolid, TDM, Therapeutic Drug Monitoring, MDR-TB, Guinea, Adverse Drug Reaction, Peripheral Neuropathy, Myelosuppression, Tuberculosis
Brief summary
Multidrug-resistant tuberculosis (MDR-TB) poses a significant challenge to global public health. Globally, the World Health Organization (WHO) estimates the number at 400,000 patients with MDR-TB for 2023. Only 44% were diagnosed and put on treatment, the therapeutic success rate of the 2021 cohort is only 68%. In Guinea, the number of patients with MDR-TB is estimated at 450, and the treatment success rate is 74% for the 2021 cohort, primarily with the 9-months short oral regimen. Since 2022, the WHO has recommended the use of the 6-month short course of BPaL/BPaL-M for national tuberculosis control programs and Guinea began implementing this new regime within the programmatic framework starting in January 2025. Linezolid, a key component of new therapeutic regimens such as BPaL/BPaL-M, shows high bactericidal activity, although it is associated with serious adverse effects in a high percentage of patients, including myelosuppression, neuropathy and, in some cases, fatal lactic acidosis. In particular, peripheral neuropathy, an adverse event often irreversible that may lead to linezolid and the BPaL/BPaL-M regimen discontinuation, is reported in approximately 24% of patients receiving linezolid at 600 mg. A linezolid blood trough level of above 2 mg/l is associated with side effects, but its pharmacokinetics varies considerably between individuals and over time. There is little data on the role of therapeutic drug monitoring (TDM) in guiding its administration, some studies showing how the standard dose of 600 mg could exceed the toxicity target and the reduced dose of 300 mg might not achieve the target efficacy. The main objective of this study is to determine the role of TDM in the optimization of linezolid dosage in TB-MDR patients treated with the BPaL/BPaL-M regimen. The specific objectives aim to evaluate: * the variation in the occurrence of adverse events between patients who undergo a modification of the linezolid dose based on the TDM and patients taking linezolid standard dose * the treatment outcome in patients who undergo a modification of the linezolid dose based on TDM and patients taking linezolid standard dose * variations in the distribution of TDM throughout treatment in order to identify potential common trends.
Interventions
DRUGLinezolid dose personalization based on TDM
The dosage of linezolid will be modified according to the TDM as follows: if \> 2 mg/l the dosage will be decreased by 300 mg (minimum 300 mg every second day, TDM repeated after one week); if \< 0.6 mg/l the dosage will be increased by 300 mg (maximum 1200 mg, TDM repeated after one week); if between 0.6 and 2 mg/l the dosage will not be changed (regular TDM timepoints)
Sponsors
Marco Schiuma
ASST Fatebenefratelli Sacco
University of Milan
Damien Foundation
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
15 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* 1\. Confirmed diagnosis of MDR-TB * 2\. Linezolid prescribed as part of the BPaL/BPaL-M regimen * 3\. Age 15 years or older * 4\. Informed consent obtained from the participant or assent from the parent/legal guardian for participants under 18 years of age.
Exclusion criteria
* 1\. Pregnancy or breastfeeding * 2\. Severe liver or kidney failure * 3\. Known hypersensitivity to linezolid * 4\. Concomitant use of medications with drug interactions potential with linezolid
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Rate of linezolid related side effects. | From enrollment to the end of treatment at 6 months | The primary objective is to evaluate the variation in the rate of occurrence of adverse events between patients who undergo a modification of the linezolid dose based on the TDM and patients taking linezolid standard dose. We hypothesize that patients who under go linezolid dose personalization based on TDM will maintain linezolid blood levels within the therapeutic range (0.6-2 mg/l). This could result in a different rate in linezolid related side effects between the two groups |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Feasibility of linezolid dosage personalization based on TDM in low resources setting | From enrollment to the end of treatment at 6 months | The objective is to determine if TDM has a role in the optimization of linezolid dosage in TB-MDR patients in a setting similar to Guinea. The feasibility and implementability of the method will be assessed by comparing the number of blood samples actually collected from each participant with the number of samples scheduled according to the predefined theoretical sampling time set for each participant. |
| Treatment outcome | From the enrollment to the end of the treatment at 6 months | The objective is to evaluate the treatment outcome (defined by WHO as: treatment failed, cured, treatment completed, died, lost to follow up, treatment success, sustained treatment success) in patients who undergo a modification of the linezolid dose based on TDM and patients taking linezolid standard dose. |
| Linezolid TDM trends | From enrollment to the end of treatment at 6 months | The objective is to describe the TDM values during the treatment, define variations in the distribution of TDM throughout treatment in order to identify potential common trends (for example median lower values at the beginning of the treatment for all the patients, linked to higher inflammation, increased values at the end of the treatment for linezolid accumulation) |
Countries
Guinea
Contacts
CONTACTMarco Schiuma
CONTACTSouleymane Hassane Harouna
STUDY_DIRECTORMarco Schiuma
ASST Fatebenefratelli Sacco, Luigi Sacco University Hospital, Milan, Italy
PRINCIPAL_INVESTIGATORSouleymane Hassane Harouna
Action Daminen Guinée
Outcome results
None listed